Structural Mechanisms and Drug Discovery Prospects of Rho GTPases.
Structural Mechanisms and Drug Discovery Prospects of Rho GTPases.
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DOI：
10.3390/cells5020026
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发表时间：
2016-06-13
期刊：
影响因子：
6
通讯作者：
Overduin M
中科院分区：
文献类型：
--
作者：
Smithers CC;Overduin M
Rho GTP酶调节细胞形态和动力学，其中一些是癌症进展的关键驱动因素。这个超家族为治疗干预提供了有吸引力的潜在靶点，RhoA，Rac1和Cdc42是主要的例子。开发作用于这些信号传导酶的药物的挑战包括缺乏明显的可药用口袋及其膜结合活性。然而，靶向类似Ras蛋白的进展为特异性抑制致癌GTP酶提供了新的策略。Rho蛋白的多种信号和调节状态的结构已被确定，翻译后修饰，包括酰化和磷酸化点已被映射，并检查其功能效应。开发抑制剂来探测这些GTP酶的过度表达和突变过度活化的意义，强调了它们在癌症进展中的重要性。在计算机上整合的能力，在体外，和在体内的药物样分子的调查表明，越来越多的跟踪GTTRIPS系统的铅优化。尽管尚未有Rho靶向药物分子获得临床批准，但该家族显然显示出越来越多的发展前景，用于精确医学和联合癌症治疗。
Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies.